Process for making sterile aripiprazole of desired mean particle size

ABSTRACT

A process is provided for making sterile aripiprazole having an average particle size less than 100 microns but preferably greater than 25 microns employing an impinging jet crystallization procedure. The resulting bulk aripiprazole of desired particle size may be used to form a sterile freeze-dried aripiprazole formulation, which upon constitution with water and intramuscular injection releases aripiprazole over a period of at least about one week and up to about eight weeks.

CROSS REFERENCE TO RELATED APPLICATION

This Continuation application claims the benefit of U.S. Ser. No.10/968,481 filed Oct. 19, 2004 which claims the benefit of U.S.Provisional application Ser. No. 60/513,886, now expired, the entiredisclosure of which is herein incorporated by reference.

FIELD OF THE INVENTION

The present invention related to a process for making sterilearipiprazole of desired particle size distribution and mean particlesize which is especially adapted for use in preparing a controlledrelease formulation which releases aripiprazole over at least one weekor more.

BACKGROUND OF THE INVENTION

U.S. provisional application No. 60/513,618, discloses a controlledrelease sterile injectable aripiprazole formulation in the form of asterile suspension, and a method for preparing a sterile freeze-driedaripiprazole formulation (employed in forming the injectableformulation) which includes the steps of:

(a) preparing sterile bulk aripiprazole preferably having a desiredparticle size distribution and mean particle size within the range fromabout 5 to about 100 microns, more preferably from about 10 to about 90microns,

(b) preparing a sterile vehicle for the sterile bulk aripiprazole,

(c) combining the sterile bulk aripiprazole and the sterile vehicle toform a sterile primary suspension,

(d) reducing the mean particle size of aripiprazole in the sterileprimary suspension to within the range from about 0.05 to about 30microns, to form a final sterile suspension, and

(e) freeze drying the final sterile suspension to form a sterilefreeze-dried suspension of the aripiprazole of desired polymorphic form(anhydrous, monohydrate, or a mixture of both).

In carrying out the above method for preparing the freeze-driedaripiprazole formulation, it is required that everything be sterile sothat sterile aripiprazole and sterile vehicle are combined asepticallyto form a sterile suspension and that the sterile suspension befreeze-dried in a manner to form sterile freeze-dried powder or cake.Thus, an aseptic procedure is employed to produce sterile bulkaripiprazole of desired mean particle size, and particle sizedistribution, by crystallization methods as opposed to ball milling. Thesterile bulk aripiprazole preferably prepared in step (a) by means ofthe impinging jet crystallization method, has a desired small particlesize and narrow particle size distribution, high surface area, highchemical purity, and high stability due to improved crystal structure.

The impinging jet crystallization utilizes two jet streams that strikeeach other head-on. One of the streams carries a solution rich in thearipiprazole and the other carries an anti-solvent, such as water. Thetwo streams strike each other which allows for rapid homogeneous mixingand supersaturation due to high turbulence and high intensity ofmicromixing upon impact. This immediate achievement of supersaturationinitiates rapid nucleation. In general, the average crystal size of thearipiprazole decreases with increasing supersaturation and decreasingtemperature of the anti-solvent. Therefore, in order to obtain thesmallest particle size, it is advantageous to have the highest possibleconcentration of the aripiprazole rich solution and the lowesttemperature of the anti-solvent.

The technique employed for forming sterile bulk aripiprazole isimportant since particle size of the aripiprazole formulation controlsits release profile in the blood system over a period of one month.

It has been found that batch crystallization of aripiprazole producesparticles 100 microns. However, in formulating the controlled releasesterile aripiprazole injectable formulation discussed above, theparticle size of the aripiprazole needs to be 95%≦100 microns. Inaddition, a narrow particle size distribution is needed to maintaincontrol of the release profile. Milling of batch aripiprazole isundesirable, as a broad particle size distribution will be obtained.Thus, it would be advantageous to employ a technique for preparingsterile bulk aripiprazole which can reduce particle size of aripiprazoleto 95%≦100 microns with a narrower particle size distribution thanattainable employing batch crystallization.

U.S. Pat. No. 5,006,528 to Oshiro et al. discloses7-[(4-phenylpiperazino)-butoxy]carbostyrils, which include aripiprazole,as dopaminergic neurotransmitter antagonists.

Aripiprazole which has the structure

is an atypical antipsychotic agent useful in treating schizophrenia. Ithas poor aqueous solubility (<1 μg/mL at room temperature).

U.S. Pat. No. 6,267,989 to Liversidge, et al. discloses a method forpreventing crystal growth and particle aggregation in nanoparticulatecompositions wherein a nanoparticulate composition is reduced to anoptimal effective average particle size employing aqueous millingtechniques including ball milling.

U.S. Pat. No. 5,314,506 to Midler, et al. discloses a process for thedirect crystallization of a pharmaceutical having high surface areaparticles of high purity and stability wherein impinging jet streams areemployed to achieve high intensity micromixing of particles of thepharmaceutical followed by nucleation and direct production of smallcrystals.

U.S. Pat. No. 6,302,958 to Lindrud et al. discloses a method andapparatus for crystallizing submicron-sized crystals of a pharmaceuticalcomposition employing sonication to provide ultrasonic energy in theimmediate vicinity of impinging fluid drug and solvent streams so as toeffect nucleation and the direct production of small crystals.

U.S. application Ser. No. 10/419,418, filed Apr. 21, 2003 by Chenkou Wei(attorney docket TU58 NP) which is based on U.S. ProvisionalApplications Nos. 60/376,414, filed Apr. 29, 2002 and 60/439,066, filedJan. 9, 2003 entitled “Crystallization System Using Atomization”discloses a method for crystallizing a pharmaceutical by atomizing onesolution and introducing the atomized solution into a vessel containinga second solution where the solutions are mixed to form a product, whichdoes not require post-crystallization milling. This application isincorporated herein by reference.

U.S. application Ser. No. 10/419,647, filed Apr. 21, 2003 by Chenkou Wei(attorney docket TU59 NP) which is based on U.S. ProvisionalApplications Nos. 60/379,351, filed May 10, 2002 and 60/439,057, filedJan. 9, 2003 entitled “Crystallization System Using Homogenization”discloses a process for crystallizing a chemical material from a firstsolution and a second solution wherein the first solution is atomizedand introduced into a second solution, and the atomized solution andsecond solution are mixed to form the product. This application isincorporated herein by reference.

BRIEF DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided a processfor preparing sterile bulk aripiprazole of desired small particle sizeand narrow particle size distribution, preferably having an averageparticle size less than about 100 microns but preferably greater than 25microns, which includes the steps of:

(a) providing a jet stream of a solution of aripiprazole in an organicsolvent, preferably ethanol, preferably heated at a desired elevatedtemperature;

(b) providing a jet stream of anti-solvent, preferably water, which iscapable of initiating precipitation of aripiprazole from solution,preferably said anti-solvent being at a desired temperature below thetemperature of the solution of aripiprazole;

(c) causing the jet stream of solution of aripiprazole in solvent andthe jet stream of anti-solvent to strike each other and impinge on oneanother to create high turbulence at their point of impact, each jetstream having sufficient linear velocity to achieve high intensitymicromixing of each stream prior to nucleation, to produce a slurry ofcrystals of aripiprazole monohydrate; and

(d) recovering crystals of aripiprazole monohydrate of desired smallparticle size and narrow particle size distribution.

Prior to step (d) ultasonic energy may be provided, by means of asonication probe, as described in U.S. Pat. No. 6,302,958, thedisclosure of which is incorporated herein by reference, the tip ofwhich is positioned within a gap defined between the two jet streams, tocause the impinging jet streams to achieve high intensity micromixing offluids prior to nucleation.

In addition, in accordance with the present invention, a preferredprocess is provided for preparing sterile bulk aripiprazole of desiredaverage particle size of less than about 100 microns, but preferablygreater than 25 microns, and narrow particle size distribution, whichincludes the steps of:

(a) providing a jet stream of a solution of aripiprazole in ethanolheated at a temperature within the range from about 70 to about 85° C.,preferably from about 75 to about 80° C.;

(b) providing a jet stream of deionized water which is at a temperaturewithin the range from about 2 to about 40° C., preferably from about 20to about 35° C.;

(c) causing the jet streams of solution of aripiprazole and water, eachat a flow rate (where jet nozzles of 0.02 inch internal diameter areemployed) within the range from about 0.20 to about 0.30 kg/min,preferably from about 0.22 to about 0.28 kg/min, to impinge on oneanother to create high turbulence at their point of impact to achievehigh intensity micromixing of each stream prior to nucleation, and forma slurry of crystals of aripiprazole monohydrate; and

(d) recovering crystals of aripiprazole monohydrate having an averageparticle size less than 100 microns, but preferably greater than 25microns, preferably about 95% of the crystals having a particle sizeless than 100 microns.

Prior to step (d) ultasonic energy may be provided, by means of asonication probe, as described above, the tip of which is positionedwithin a gap defined between the two jet streams, to cause the impingingjet streams to achieve high intensity micromixing of fluids prior tonucleation.

In carrying out the above process of the invention, the volumetric ratioof solution of aripiprazole in organic solvent to anti-solvent is withinthe range from about 0.5:1 to about 1.5:1, preferably from about 0.9:1to about 1.1:1.

The above processes may also be employed to prepare crystals ofaripiprazole monohydrate having an average particle size of less than 25microns.

The processes of the invention as described above employs jet streamswhich impinge on each other to achieve high intensity micromixing of thestreams to enable formation of a homogeneous composition prior to thestart of nucleation in a continuous crystallization process. Nucleationand precipitation are initiated utilizing the effect of antisolventaddition on the solubility of the aripiprazole in the solvent therefor.

The sonication steps disclosed above are carried out as described inU.S. Pat. No. 6,302,958.

The aripiprazole produced by the process of the invention may beemployed in forming sterile bulk aripiprazole having a desired particlesize distribution, preferably 10%<10 microns, 50%<35 microns and 95%<100microns, and mean particle size within the range from about 25 to about100 microns.

The sterile bulk aripiprazole prepared by the process of the inventionmay be used in forming a sterile-freeze dried aripiprazole formulationwhich may be suspended in water to form an injectable aripiprazoleformulation as described in U.S. provisional application Ser. No.10/419,647.

Each of the above embodiments of the process of the invention arereferred to as the impinging jet crystallization process of theinvention.

The process of the invention employs impinging jet crystallizationtechnology, an example of which is disclosed in U.S. Pat. No. 5,314,506to Midler et al.

It will also be appreciated that the sterile bulk aripiprazole ofdesired small particle size and narrow particle size distribution asdescribed above may be prepared employing the process and apparatusdescribed and claimed in each of the Chendou Wei applications entitled“Crystallization System Using Atomization” and “Crystallization SystemUsing Homogenization” described above and incorporated herein byreference.

BRIEF DESCRIPTION OF THE FIGURES

The accompanying Figure is a schematic representation of an impingingjet crystallization process flow diagram used in carrying out theprocess of the invention, which includes a crystallizer vessel.

DETAILED DESCRIPTION OF THE INVENTION

The process of the invention is illustrated in the following reactionscheme:

In carrying out the process of the invention, low pyrogen aripiprazolestarting material is employed to ensure that the sterile aripiprazole ofdesired particle size will be produced. The low pyrogen aripiprazolestarting material may be either the anhydrous form or the monohydrateform. Either material will yield the desired monohydrate form from theimpinging jet crystallization process of the invention.

The process of the invention employs two jet nozzles to create twoimpinging jet streams to achieve high intensity micromixing of thestreams prior to nucleation and formation of crystals of aripiprazolemonohydrate. The two impinging jet streams should be substantiallydiametrically opposed to one another with the nozzles directed to faceeach other. The jet nozzles will be aligned and positioned so that thefluid streams will impact head-on and will impinge. When the jet nozzlesare properly aligned and appropriate flow rates chosen, the two streamswill form a plane when impinged.

Each of the process streams, namely the aripiprazole-organic solventstream and the anti-solvent stream will be sterilized. To sterilize thetwo process streams, both streams are preferably polish filtered andthen sterile filtered through an appropriate size filter, such as a 0.2micron filter. The aripiprazole stream should be filtered at an elevatedtemperature, for example, about 80° C., to prevent precipitation.

The temperature and composition of each solution are chosen so that 1)no material will crystallize upstream of the impinging jets, and 2)sufficient supersaturation will be developed in the impinging jets tocause nucleation. Micromixing creates temperature and compositionaluniformity throughout the mixture prior to the start of nucleation.

To obtain the smallest particle size of aripiprazole, the highestpossible concentration of aripiprazole in the organic solvent should beemployed. Thus, the starting solution of aripiprazole in organicsolvent, preferably ethanol, will contain from about 0.01 to about 0.1kg/L aripiprazole, preferably from about 0.04 to about 0.06 kg/Laripiprazole. In a most preferred embodiment, the aripiprazole will bepresent in an amount of about 0.05 kg/L.

The organic solvent will preferably be ethanol, most preferably fromabout 92 to about 97% ethanol, with the remainder being water.

Other organic solvents, such as methanol, ethyl acetate, acetone,acetonitrile, acetic acid or isopropyl alcohol or mixtures of two ormore thereof, or mixtures with water may be employed.

The anti-solvent will preferably be deionized water.

The two streams, namely, the stream of the solution of aripiprazole inthe organic solvent and the stream of anti-solvent, are characterized asjet streams in that they will be made to strike each other head on athigh linear velocities with a minimum of 5 m/s. The flow rates will bedetermined by the diameter of the jet nozzles employed to deliver thestreams and the rate at which the streams are pumped through thenozzles. In a preferred embodiment, the flow rate of each of the streamof aripiprazole/solvent and the stream of antisolvent will beessentially the same, but will of course be in opposite directions.

The flow rates will be chosen so that proper impinging is achieved. Forexample, where jet nozzles of 0.02 inch internal diameter are employed,flow rates will be within the range from about 0.20 to about 0.30kg/min, preferably from about 0.22 kg/min to about 0.28 kg/min, morepreferably from about 0.24 kg/min to about 0.26 kg/min, and optimallyabout 0.25 kg/min.

The temperature of each of the streams is important in determiningultimate size of the particles of aripiprazole produced. Thus, thearipiprazole-solvent (preferably ethanol) stream should be heated at atemperature within the range from about 70 to about 85° C., preferablyfrom about 75 to about 80° C. The anti-solvent stream (preferably water)should be at a temperature substantially less than the temperature ofthe aripiprazole-solvent stream, and within the range from about 2 toabout 40° C., preferably from about 20 to about 35° C., and optimallyabout 30° C.

The two streams strike each other head-on, from opposite directions, tocause rapid homogeneous mixing and supersaturation due to highturbulence and high intensity of mixing upon impact. The immediateachievement of supersaturation initiates rapid nucleation. In general,the average crystal size decreases with increasing supersaturation anddecreasing temperature of the anti-solvent. The smallest particle sizeof aripiprazole is obtained employing the highest possible concentrationof the aripiprazole solution and the lowest temperature of theanti-solvent. Sonication is utilized where even smaller particles aredesired.

DESCRIPTION OF THE FIGURE

Referring to the accompanying Figure, an impinging jet crystallizationprocess flow diagram and crystallizer vessel used in carrying out theprocess of the invention are shown which includes a jacketed impingementcrystallization vessel 10. There are two jacketed-vessels 12, 14 thatflank the impingement vessel 10 to the left and right which contain thearipiprazole-rich solution (12) and the anti-solvent (14), respectively.Both of these side vessels 12, 14 are spaced apart from the impingementvessel 10. Impinging jet nozzles 16, 18, each having a 0.02-inchdiameter, are spaced 10 mm apart. The impingement vessel 10 may includeagitator 11 and a sonicator (as employed in U.S. Pat. No. 6,302,958), ifdesired, not shown for drawing clarity. Outlet 31 of impingement vessel10 is connected to receiving vessel 32, via line 33. Overflow line 35links impingement vessel 10 and line 33 and aids in maintaining aconstant volume in impingement vessel 10.

The above description is of the sterile portion of the flow diagram. Thenon-sterile portion as shown includes a vessel 34 for holding a solutionof aripiprazole in ethanol, preferably 95% ethanol, which is pumped viapump 36 through polish filter 38 and sterile filter 40 into vessel 12and processed as described above.

The jet nozzles 16, 18 should be placed so that the fluid streams theyemit will impinge, inside the stirred impingement vessel 10 or inside aseparate jet chamber (not shown) which is linked directly to the vessel10. The fluid jets must impinge to create an immediate high turbulenceimpact. The two jet nozzles are preferably arranged so that they aresubstantially diametrically opposed to each other with their outlet tipsdirected to face each other; i.e., the two jet nozzles are at or closeto a 180 degree angle to each other from an overhead view. Preferably,each jet outlet nozzle can have a slight downward angle from thehorizontal, for example, about 10 degrees, to help the flowing materialmove down and out of the chamber.

Likewise, two jet nozzles placed directly inside the stirred impingementvessel 10 are preferably arranged so that they are substantiallydiametrically opposed to each other with their outlet tips directed toface each other. When the jet nozzles are so placed, each nozzle canhave a slight upward or downward angle from the horizontal of from 0degrees up to about 15 degrees, but preferably the two nozzles have justenough downward angle from the horizontal (ca. 13 degrees) to ensurethat the fluid stream of one will not enter the outlet hole of theopposite nozzle.

Jet nozzle 16 is used to transport aripiprazole solution into the vessel10 (or separate jet chamber) and the other jet 18 is used to similarlytransport water. The distance between the nozzle tips inside the jetchamber or vessel 10 should be such that the hydro-dynamic form of eachfluid jet stream remains essentially intact up to the point ofimpingement. Therefore, the maximum distance between the nozzle tipswill vary depending on the linear velocity of the fluids inside the jetnozzles. To obtain good results for generally non-viscous fluids, linearvelocity in the jet nozzles should be at least about 5 meters/sec., morepreferably above 10 meters/sec., and most preferably between about 20 to25 meters/sec., although the upper limit of linear velocity is onlylimited by the practical difficulties involved in achieving it. Linearvelocity and flow rate can both be controlled by various known methods,such as altering the diameter of the entry tube and/or that of thenozzle outlet tip, and/or varying the strength of the external forcethat moves the fluid into and through the nozzle. Each jet apparatus canbe manipulated independently to attain a desired final fluid compositionratio. When the desired flow ratio of one jet to the other differs fromunity, preferably the difference is compensated for by appropriatesizing of the entry tubes. For example, if a 4:1 volumetric ratio offeed solution to anti-solvent is desired, the entry tube delivering feedsolution should be twice the diameter of the entry tube deliveringanti-solvent. When the jet streams impinge inside a jet chamber,residence time for the fluid inside the jet chamber is typically veryshort, i.e., less than ten seconds.

Stirring in the vessel is provided by standard agitators 11, preferablyRushton 10 turbines, Intermig impellers, or other agitators suitable forstirring a slurry suspension. Any impeller providing good circulationinside the vessel may be used. However, when the jet streams arearranged to impinge directly inside the stirred vessel, an agitator thatdoes not interfere with the space occupied by the impinging jet streamsinside the vessel is preferred, especially, e.g., a Rushton turbine.Impinging jet streams inside the vessel are most preferably placed inthe effluent stream of the agitator, and the height of the liquid in thestirred vessel 10 when operated in continuous mode (i.e., flow in equalsflow out, constant volume maintained), is most preferably between abouttwo to four times the height of the impeller.

The crystallization is preferably run in a continuous process and theappropriate residence time for the completion of crystal digestion isattained by adjusting the volume capacity of the stirred vessel, but themixture can be held up in the vessel for any desired length of age timeif batchwise processing is desired.

Manual seeding can be done at any point in the system, e.g., in thestirred vessel 10, the transfer line or the jet chamber itself. In somesituations, the continuous jet process may be “self-seeding”, i.e., thefirst crystals to form inside the jet chamber (if used), the transferline (if used) or the stirred vessel 10 serve as seed for the materialthat flows through thereafter.

The micromixed material must be highly supersaturated to attain thebeneficial results of the jet crystallization process. Aside fromthermoregulated initiation of nucleation, temperature variation alsoaffects product results when anti-solvent is used to initiate nucleationbecause of its effect on supersaturation. Generally, good results can beachieved using a volumetric ratio of aripiprazole to anti-solvent thatprovides a high degree of supersaturation in the jet chamber in atemperature range of about 24° C. to 70° C., although the temperatureupper limit is limited only by the chosen solvent's boiling point.

An example of the impingement vessel which may be employed is disclosedin U.S. Pat. No. 5,314,506 to Midler et al. and in U.S. Pat. No.6,302,958 to Lindrud et al. which are incorporated herein by reference.

To prepare a 100-gram batch of aripiprazole monohydrate, a 100 grams ofaripiprazole anhydrous N1 is charged into a 4-L vessel 12 and dissolvedin 2 L of 95% ethanol at 75 to 80° C. The clear solution is thentransferred to the product-rich 2-L jacketed vessel 10 and maintained at75 to 80° C. In the anti-solvent vessel 14, 2 L of deionized (DI) wateris then charged and heated to 28 to 32° C. When both liquids are at thedesired temperatures, the two streams are pumped simultaneously viapumps 20 and 22 through mass flow meters 24, 26, respectively, andsterile filters 28, 30, respectively, through the 0.02-inch internaldiameter nozzles 16, 18 and impinge at a rate of 0.22 to 0.28 kg/min toproduce the monohydrate crystals. The crystals are continuouslytransferred to receiving vessel 32 to maintain a constant volume in theimpingement vessel 10. It takes approximately 5 to 7 minutes to impingea 100-gram batch. The slurry is cooled to 20 to 25° C., filtered, andwashed with 200 mL of deionized water. The cake is then dried at 35° C.under vacuum to obtain approximately 100 grams of aripiprazolemonohydrate, H0, with a Karl Fisher % (KF %) of ca. 4% w/w.

EXAMPLES

The following working Examples represent preferred embodiments of thepresent invention.

Example 1

Sterile bulk active pharmaceutical ingredient (API) aripiprazole wasprepared using impinging crystallization with sonication employing anapparatus set up as shown in the attached Figure.

The following procedure was employed to form a sterile bulkaripiprazole.

1. Charge 100 g of aripiprazole in a 4 L flask 34.

2. Add 2 L of 95% ethanol.

3. Heat the suspension to 80° C. until it becomes a clear solution.

4. Transfer the hot aripiprazole solution to a 2 L jacketed vessel 12and maintain at 75-80° C.

5. Charge 2 L of deionized (DI) water to a 2 L jacketed vessel 14.

6. Cool the DI water to 2° C.

7. Add 100 mL of 95% ethanol and 100 mL of DI water to the impingingvessel 10 and cool to 2° C.

8. Initiate sonication (Sonication is provided by a 0.5 inch probe with120 W power output employed as described in U.S. Pat. No. 6,302,958).

9. Pump the aripiprazole solution through a 0.02 inch diameter nozzle 16at 0.25 kg/min and impinge it with the 2° C. water pumped at 0.25 kg/minthrough a 0.02 inch diameter nozzle 18.

10. Sonicate the newly formed crystal slurry in the impinge vessel 10while continuously transferring the crystals to a receiving vessel 32 tomaintain a constant volume in the impingement vessel 10.

11. Cool the slurry to 20 to 25° C. at the end of impingement.

12. Filter the slurry.

13. Wash the cake with 200 mL of DI water.

14. Dry the wet cake at 35° C. under vacuum to obtain 97.9 g ofaripiprazole with a KF of 4.0% w/w, with reduced particle size (95%<100microns).

Example 2

Sterile bulk API aripiprazole was prepared using impinging jetcrystallization and an apparatus set up as shown in the accompanyingfigure.

The following procedure was employed to form a sterile bulkaripiprazole:

1. Suspend 100 g of aripiprazole in 2000 mL of 95% ethanol. Heat thesuspension to 80° C. until it becomes a clear solution.

2. Polish filter the aripiprazole solution into a holding vessel 12 andmaintain at 80° C.

3. Polish filter 2000 mL water to another holding vessel 14 and heat to80° C.

4. Pump the aripiprazole solution through a 0.02 inch diameter nozzle 16at 0.25 kg/min and impinge it with the 30° C. water pumped at 0.25kg/min through a 0.02 inch diameter nozzle 18 to form a crystal slurrywhich is collected in an impingement vessel 10.

5. Agitate the newly formed crystal slurry in the impingement vessel 10while continuously transferring it to a receiver 32 to maintain aconstant volume in the impingement vessel 10.

6. At the end of impingement, cool the slurry in the receiver 32 to roomtemperature.

7. Filter the slurry.

8. Dry the wet cake at 35° C. under vacuum to yielding 100 g (96%recovery) of aripiprazole with reduced particle size (95%<100 microns).

Example 3

An aripiprazole injectable aqueous suspension (200 mg aripiprazole/2 mL,200 mg/vial) was prepared as follows.

The following ingredients were added to a 3 L glass jacketed vesselmaintained at 15° C. (±5° C.) to form a sterile primary suspension:

Aripiprazole (prepared by impinging jet

-   -   crystallization as described in Example 2): 100 g

Carboxymethylcellulose, Sodium Salt 7L2P 9.0 g

Mannitol 45 g

Sodium Phosphate, Monobasic 0.8 g

Sodium Hydroxide Solution, 1N q.s. to adjust pH to 7.0

Water, USP q.s. to 1000 g

The sterile suspension was mixed at 500-1000 rpm for about 0.5 hour andthen at 300-500 rpm for an additional 1 hour under 20″Hg (±5″Hg) vacuum.

2.5 mL of the above suspension were aseptically filled into sterilizedvials which were then aseptically partially stoppered with sterilizedstoppers. The vials were aseptically transferred to a freeze dryer andlyophilized according to the following cycle:

(a) thermal treatment: freeze product at −40° C. over 0.1-1 h and keepat −40° C. for at least 6 h,

(b) cool the condenser to −50° C. or below,

(c) primary drying: lower chamber pressure to approximately 100 micronsHg and increase product temperature to −5° C. over approximately 2 h;continue primary drying at −5° C. and 100 microns Hg for at least 48 h,

(d) stopper the vials under atmospheric pressure or partial vacuum usingsterile nitrogen or air and remove from the freeze dryer,

(e) seal the vials with the appropriate seals and label.

1. A process for preparing sterile crystalline aripiprazole of desiredsmall particle size and narrow particle size distribution withoutmilling, which comprises: (a) providing a jet stream of a solution ofaripiprazole in an organic solvent; (b) providing a jet stream ofanti-solvent which is capable of initiating precipitation ofaripiprazole from solution, wherein each of said aripiprazole-organicsolvent stream and said anti-solvent stream is sterilized; (c) causingthe jet stream of solution of aripiprazole in solvent and the jet streamof anti-solvent to strike each other and impinge on one another tocreate high turbulence at their point of impact, each jet stream havingsufficient linear velocity to achieve high intensity micromixing of eachstream prior to nucleation, to produce a slurry of crystals ofaripiprazole monohydrate; and (d) recovering crystals of aripiprazolemonohydrate of desired small particle size of average particle size ofless than 100 microns but greater than 25 microns, and narrow particlesize distribution, wherein at least 50% of said crystals have a particlesize of less than 35 microns.
 2. The process as defined in claim 1further including the step of providing ultrasonic energy in theimmediate vicinity of said impinging jet streams, so as to effectnucleation and the direct production of small crystals of aripiprazole.3. The process as defined in claim 1 wherein the jet stream of thesolution of aripiprazole in an organic solvent is heated at a desiredelevated temperature and the jet stream of anti-solvent is at a desiredtemperature below the temperature of the other jet stream.
 4. Theprocess as defined in claim 1 wherein the organic solvent for thearipiprazole is ethanol, methanol, ethyl acetate, acetone, acetonitrile,acetic acid or isopropyl alcohol, or mixtures of one or more thereof, ormixtures with water.
 5. The process as defined in claim 1 wherein theorganic solvent for the aripiprazole is ethanol or a mixture of ethanoland water.
 6. The process as defined in claim 1 wherein the anti-solventis water.
 7. The process as defined in claim 1 wherein the volumetricratio of solution of aripiprazole in organic solvent to anti-solvent iswithin the range from about 0.5:1 to about 1.5:1.
 8. The process asdefined in claim 1 wherein the aripiprazole-solvent stream and theanti-solvent stream are in about a 1:1 volume ratio.
 9. The process asdefined in claim 1 wherein the organic solvent comprises ethanol and thesolution of aripiprazole in ethanol is heated at a temperature withinthe range from about 70 to about 85° C.
 10. The process as defined inclaim 1 wherein the anti-solvent is water at a temperature within therange from about 2 to about 40° C.
 11. The process as defined in claim 1wherein the jet stream of a solution of aripiprazole in organic solventand the jet stream of anti-solvent impinge each other at a flow rate ofeach which is the same or different but is within the range from about0.2 to about 0.3 kg/min where jet nozzles of 0.02 inch internal diameterare employed.
 12. A process for preparing sterile aripiprazole ofdesired small particle size and narrow size distribution withoutmilling, which comprises: (a) providing a jet stream of a solution ofaripiprazole in ethanol/water heated at a temperature within the rangefrom about 70 to about 85° C., wherein said stream is also sterilized;(b) providing a jet stream of deionized water which is at a temperaturewithin the range from about 2 to about 40° C., wherein said stream isalso sterilized; (c) causing the jet stream of solution of aripiprazolein ethanol and the jet stream of water each at a flow rate within therange from about 0.2 to about 0.3 kg/min, where jet nozzles of 0.02 inchinternal diameter are employed, to impinge on one another to create highturbulence at their point of impact to achieve high intensitymicromixing of each stream prior to nucleation, to form a slurry ofcrystals of aripiprazole monohydrate; and (d) recovering crystals ofaripiprazole monohydrate having an average particle size about 95% lessthan 100 microns, but greater than 25 microns.
 13. The process asdefined in claim 12 further including the step of providing ultrasonicenergy in the immediate vicinity of said impinging jet streams, so as toeffect nucleation and the direct production of small crystals ofaripiprazole.
 14. The process as defined in claim 12 wherein thearipiprazole has a low pyrogen content and is the anhydrous form ofaripiprazole or the monohydrate form of aripiprazole.
 15. The process asdefined in claim 12 wherein the aripiprazole-ethanol solution containsfrom about 0.10 to about 0.1 kg/L aripiprazole.
 16. The process asdefined in claim 12 wherein the stream of aripiprazole in ethanol andthe stream of deionized water flow in opposite directions and form aplane when they impinge one another, and strike each other to causerapid homogeneous mixing and supersaturation due to high turbulence andhigh intensity of micromixing upon impact, which initiates rapidnucleation.
 17. The process as defined in claim 12 wherein averagecrystal size decreases with increasing concentration of aripiprazole inethanol and supersaturation and decreasing temperature of theanti-solvent.
 18. The process as defined in claim 12 wherein thearipiprazole-ethanol stream and the water stream are in about a 1:1volume ratio with each other.